The Mechanism of Lithium-Halogen Exchange

Keq
R1 X Li R2 Li R1 R2 X

MacMillan Group Meeting

February 22, 2007
Sandra Lee

Key Articles:
Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1–46.

Seyferth, D. Organometallics 2006, 25, 2–24.

Schlosser, M. Organoalkali Chemistry. In Organometallics in Synthesis, A Manual: Schlosser, M., Ed; Wiley &
Sons LTD: West Sussex, U. K. 2002, pp 5–352.
 Beginnings of Main-Group Organometallic Chemistry

■ Me2Zn: The first main group organometallic compound was discovered

by Frankland in 1849

" When, on Jul y 28, 1848, Edwar d Fr ankl and, then a 23-year -ol d facul ty member of Queenwood
Col l ege i n Hampshi r e, Engl and, fi l l ed a thi ck-wal l ed gl ass tube wi th fi nel y gr anul ated zi nc
and ethyl i odi de and then seal ed i t, he di d not r eal i ze that he had set up the r eacti on
that woul d pr oduce the fi r st mai n-gr oup or ganometal l i c compounds, ethyl zi nc i odi de and
di ethyl zi nc... Hi s goal was the pr epar ati on and i sol ati on of the ethyl “r adi cal ”. "

■ Lithium organic compounds: physical and chemical properties

The small size of Li+ compared to other the other alkali-metal cations results in a much greater polarizing power
(i.e. charge density)
covalent ionic
Li+= 1.66
Φ (ionic potential)* = Z/ r Na+ = 1.04 high positive charge low positive charge
K+ = 0.76 small cation large cation
Z = ionic charge (+1) large anion small anion
r = ionic radius (Å) (e.g. AlI3) (e.g. NaCl)

Thus, organolithium compounds are more covalent (less ionic as per Fajans' rule), less reactive and more
soluble in organic solvents than Na or K counterparts (ie. easier to handle)

For a historical review: Seyferth, D. Organometallics, 2001, 20, 2940.

Frankland, E. Ann. 1849, 71, 213.
*Cartledge, G. H. J. Am. Chem. Soc. 1928, 50, 2855.
 Missed Opportunities: The Discovery of the Lithium–Halogen Exchange Reaction

■ The first study of metallic lithium with organic halides did not consider the formation of PhLi

"
Li
I LiI
Δ
"small quantity" "

Spencer, J. F.; Price, G. M. J. Chem. Soc. 1910, 97, 385.

■ In an article entitled "The mechanism of the reaction between lithium n-butyl and various organic
halogen compounds" and misses the connection
"
n-BuLi
Me Br Me Bu
Δ "

76% Marvel, C. S.; Hager, F. D.; Coffman, D. D. J. Am.Chem. Soc. 1927, 49, 2323.

■ Ziegler tried to determine the concentration of alkyl lithium solutions in benzene...

Another would be discoverer

RLi
Me Br Me R LiBr
rt

Ziegler, K.; Crössman, F.; Kleiner, H.; Schäfer, O. Liebigs Ann. Chem. 1929, 473, 1.
The First Lithium–Halogen Exchange Reaction

■ In 1938 Wittig is surprised by his discovery of lithium–halogen interconversion:

After observing lithiation of p-Bromo anisole by phenyl lithium (via Li–hydrogen exchange)

Li
PhLi
MeO Br MeO Br C6H6
Et2O

They were surprised when 1,3-dimethoxy-4,6-dibromobenzene reacted differently (ie. not by Li–hydrogen
exchange but lithium–bromine exchange. Wittig called the reaction contrary to every chemical intuition:

" Es hat si ch al so di e fol gende, jedem chemi schen

ü Gefuhl wi der str ebende Reackti on abgespi el t."

MeO Br MeO Li MeO

PhLi H2O
95%
Et2O
MeO Br MeO Br MeO Br

■ Subsequent studies of the reactions of PhLi with fluorobenzene led to the first example of a
reaction proceeding via a benzyne intermediate

Wittig, G.; Pockels, U.; Dröge, H. Ber. Dtsch. Chem. Ges. 1938, 71, 1903.
A Simultaneous Independent Discovery

! Three months after Wittig's publication, Gilman reported an independent result

in a carbonation reaction to form o-methoxybenzoic acid

Br Li HO2C
n-BuLi CO2
MeO MeO MeO
Et2O H+

! By a gentleman's agreement, Wittig restricted his research to phenyllithium

and Gilman carried out studies with alkyllithiums*

! Gilman conducted broader studies of lithium–halogen exchange reactions and made some early
observations:

1 aryl fluorides do not undergo exchange

2 rates of interchange decrease from I > Br > Cl

3 interchange is a reversible process that leads to an

equilibrium favoring the more stable RLi

*Wittig, G.; Fuhrmann, G. Ber. Dtsch. Chem. Ges. 1940, 73, 1197.
Gilman, H.; Langham, W.; Moore, F. W. J. Am. Chem.Soc. 1939, 61, 106.
Gilman, H.;Jones, R. G. Org. React. 1951, 6, 339.
Jones, R. G.; Gilman, H. Chem. Rev. 1954, 54, 835.
 Mechanistic Postulates for Li-Halogen Exchange

?
R1 X Li R2 Li R1 R2 X

Electron transfer (radical) process

R1Li R2X

Nucleophilic mechanism via halogen "ate"–type intermediate

R1 X R2 M

Four–centered transition state model

Li R2

R1 X

! Complications associated with investigating the mechanism of lithium–halogen exchange:

side-product formation and aggregation.
"... any study which probes the reaction of an organolithium substrate should consider the fundamental question of the
nature of the species (i.e. monomer, dimer, tetramer, etc.) that is responsible for the observed chemistry. Unfortunately,
due to the inherent practical difficulties associated with obtaining such data for even the simplest of systems, most studies
of the metal-halogen interchange do not address the problem of relating organolithium association with observed reactivity."

Bailey, W.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.

 Mechanistic Postulates for Li-Halogen Exchange

?
R1 X Li R2 Li R1 R2 X

Electron transfer (radical) process

R1Li R2X

Nucleophilic mechanism via halogen "ate"–type intermediate

R1 X R2 M

Four–centered transition state model

Li R2

R1 X

! Complications associated with investigating the mechanism of lithium–halogen exchange:

side-product formation and aggregation.
"... any study which probes the reaction of an organolithium substrate should consider the fundamental question of the
nature of the species (i.e. monomer, dimer, tetramer, etc.) that is responsible for the observed chemistry. Unfortunately,
due to the inherent practical difficulties associated with obtaining such data for even the simplest of systems, most studies
of the metal-halogen interchange do not address the problem of relating organolithium association with observed reactivity."

Bailey, W.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.

 Radical-Mediated Mechanism
! In 1956 Bryce-Smith attributed this result to a radical mechanism
Me
Me Ph
Ph Me
Me Me n-C8H18 n-C4H10 C4H8
n-BuBr n-BuLi
Ph Me
95 °C, 18 hr
18% 43% 19.5% 3.5%

! A SET mediated mechanism provides an explanation for the observation of "dicumene"

radical ions caged species
SET
R1Li R2X R1Li R2X R1 , Li , R2 , X

solvent "free" radicals disproportionation/

R1H R2H combination
R1 , R2 , LiX products

SET
RLi
solvent rearranged products
R1*H R2*H R1 , R1* , R2 , R2*
R1* R2*

Bryce-Smith, D. J. Chem. Soc. 1956, 1603.

 A Case Study: Norbornene and t-BuLi

H/D
t-BuLi (2 eq), –78 °C

Br pentane (4): ether (1) H/D

then D2O quench

83% (61% D) 15% (63% D)

! Ashby studies "cyclizable" probes to confirm the formation of radical intermediates

diffusion from
–LiX solvent cage
t-BuLi t-Bu
Br
cage

A B t-BuLi C SH or
t-BuLi

D D2O Li t-BuLi

Li
Me
SH or
t-BuLi D2O

Ashby, E. C.; Pham, T. N. J. Org. Chem. 1987,52, 1291.

 A Case Study: Norbornene and t-BuLi
! Cyclization was not observed in the case of the the iodide analog, heterolytic mechanism?

H/D
t-BuLi, –78 °C

I pentane (4): ether (1) H/D

then D2O quench

A: 100% (100%) B: 0%

! Temperature studies

entry temp (°C) A B Higher temperatures led

more to a radical mechanism
1 –78 100 (100) 0
except in the case at 0 °C,
2 –45 95 (95) 3 (46) when the cyclization occured
3 –23 90 (96) 6 (22) even after the reaction was
4 0 72 (36)* 30 (22)* complete.

! Solvent studies
entry solvent A B Decreasing the coordinating
ability of solvent increases the
1 pentane:ether 100 (100) 0 extent of SET pathway.
2 pentane only 88 (66) 10 (12.1) Complexing agents increase
3 pentane:ether + HMPA 99 (61) 0.1 carbanionic character and to
4 pentane:ether + TMEDA 92 (84) 5 (5.2) yield cyclization prodcuts

Ashby, E. C.; Pham, T. N. J. Org. Chem. 1987,52, 1291.

 In Search of Radical Intermediates

! Looking for skeletal rearrangements as a validation of the radical mechanism

t-BuLi, –23 °C Me Me other

Br
coupled
Me Me Me Me Me
pentane : THF products
30% 13%

Me

SET Me Me Me
Me Me

! Some conclusions from this study:

(1) SET mechanism is at least a minor pathway but there must exists a metal-exchange pathway not
involving SET

(2) It is possible that the radical was reduced in a bimolecular reaction (at a rate constant greater than
1 x 107 M–1sec–1 at –23 °C).

Newcomb, M; Willams, W. G.; Crumpacker, E. L. Tetrahedron Lett. 1985, 26, 1183.

Newcomb, M; Willams, W. G. Tetrahedron Lett. 1985, 26, 1179.
 Other Evidence for the Electron Transfer Mechanism
■ ESR (Electron-Spin Resonance) Spectroscopy experiments support free-radical mechanism
radical concentrations for a variety of organolithiums were detected to be bewteen 10–6 10–5 M under the reaction conditions

2° or 3° alkyllithium alkyl halides radical intermediates

PhLi or 1° alkyllithium alkyl halides no radicals detected

Me Me flow cell, rt Me

Me Li Me Br
benzene:ether Me

ESR spectrum of the isopropyl radical

■ ESR demonstrates radicals may be generated but it is not definitive that radicals are involved as
intermediates in the metal-halogen exchange
Fischer, H. J. Phys. Chem. 1969, 73, 3834.
 Mechanistic Postulates for Li-Halogen Exchange

?
R1 X Li R2 Li R1 R2 X

Electron transfer (radical) process

R1Li R2X

Nucleophilic mechanism via halogen "ate"–type intermediate

R1 X R2 M

Four–centered transition state model

Li R2

R1 X
 Nucleophilc Reaction Pathway?

! Gilman suggests a nucleophilic mechanism involving a carbanion leaving group

n-Bu Li Br R n-Bu X R Li

! Wittig postulated a reversible formation of an "ate-complex" (a term coined by Wittig)

n-Bu Li Br R n-Bu X R Li n-Bu X R Li

Sunthankar, S. V.; Gilman, H. J. Org. Chem. 1951, 16, 8.

Wittig, G.; Schöllkopf, U. Tetrahedron 1958, 3, 91.
 Lithium-Halogen Exchange is an Equilibrium Process

! Winkler and Winkler demonstrate interconversions are an equilibrium process

Kobs
A Li Me B Br C Br Me D Li

entry A B C D Kobs

1 0.6 (t0) 0.6 (t0) 0.0 (t0) 0.0(t0)

0.3 (teq) 0.3 (teq) 0.3 (teq) 0.3 (teq) 0.60
2 0.0 (t0) 0.0 (t0) 0.5 (t0) 0.5 (t0)
0.2 (teq) 0.3 (teq) 0.2 (teq) 0.2(teq) 0.67

Winkler, H. J. S.; Winkler, H. J. Am. Chem. 1965, 88, 964.

! Equilbrium is a reflective measure of relative carbanion stability (sp >> sp2 >> sp3)
Kobs
I R Li Li R I

R Kobs pKa R Kobs pKa R Kobs pKa

Li 0.004 36.5 Me Li 3200 42 t-Bu Li 3x10–5 42

Ph Li 1.0 37 Et Li 7600 42 Li 1x10–6 43

Li 9.5 39 (H3C)2HC Li 4x10–4 42 Li 8x10–7 44

Applequist, D. E.; O'Brien, D. F. J. Am. Chem. Soc. 1962, 85, 743.

 Lithium-Halogen Exchange is an Equilibrium Process

! Winkler and Winkler demonstrate interconversions are an equilibrium process

Kobs
A Li Me B Br C Br Me D Li

entry A B C D Kobs

1 0.6 (t0) 0.6 (t0) 0.0 (t0) 0.0(t0)

0.3 (teq) 0.3 (teq) 0.3 (teq) 0.3 (teq) 0.60
2 0.0 (t0) 0.0 (t0) 0.5 (t0) 0.5 (t0)
0.2 (teq) 0.3 (teq) 0.2 (teq) 0.2(teq) 0.67

Winkler, H. J. S.; Winkler, H. J. Am. Chem. 1965, 88, 964.

! Equilbrium is a reflective measure of relative carbanion stability (sp >> sp2 >> sp3)
Kobs
I R Li Li R I

R Kobs pKa R Kobs pKa R Kobs pKa

Li 0.004 36.5 Me Li 3200 42 t-Bu Li 3x105 42

Ph Li 1.0 37 Et Li 7600 42 Li 1x106 43

Li 9.5 39 (H3C)2HC Li 4x104 42 Li 8x107 44

Applequist, D. E.; O'Brien, D. F. J. Am. Chem. Soc. 1962, 85, 743.

 Kinetic Studies to Probe the Mechanism

Kobs
n-BuLi Br n-BuBr Li

40 °C

■ Hammett relationship for the reaction on

rate = –d[ArBr]/ dt = k[ArBr]1[n-BuLi]1 substituted bromobenzenes suggests a
negative character in the transition state
■ Reaction is first order in bromobenzene and n-BuLi (ρ ≈ 2) for the slow step of the reaction

■ Results are consistent with a concerted exchange of lithium and halogen with nucleophilic attack of a
carbanion-like aryllithium on the bromine atom of the aryl halide
Rogers, H. R.; Houk, J. J. Am.Chem. Soc. 1982, 104, 522.
 Evidence for the Formation of an Intermediate "ate–complex"

K
I n-BuI Li n-Bu LiI

■ Increasing concentration of iodobenzene ■ The addition of HMPA lowers the reactivity

decreased the rate of alkylation

■ It was postulated that a relatively unreactive "ate-complex" intermediate was formed and that HMPA
preferentially coordinates to the Li cation to lower the rate of alkylation

K
I Li I Li • HMPA

Reich, H. J.; Phillips, N. H.; Reich, I. L. J. Am.Chem. Soc. 1985, 107, 4101.
 Evidence for the Intermediacy of an "ate–complex"

! Farnham isolates a hypervalent (10-I-2) structure from a Li-Halogen exchange reaction

F F F F F F
C6F5I
F Li F I F Li • 2 TMEDA
TMEDA
F F F F F F

C–I Bond Distance = 2.331 (5) Å

2.403 (6) Å

C–I–C Bond Angle = 175°

! The isolated "ate–complex" was found to be a competent nucleophile

F3C F F3C C6F5

92%
(C6F5)2I– Li+ LiF C6F5I
F3C CF2CF3 F3C CF2CF3

! Analogous stable hypervalent 10–Br–2 anions have since been established

Famham, W. B.; Calabrese, J. C. J. Am. Chem. 1969, 73, 3834.

 Probing the Transition Structure Geometry: The Endocyclic Restriction Test
! 10–X–2 "ate-complexes" favor linear geometries, which has also been suggested to be favored
in nucleophilic substitution reaction at the halogen center

I Li
x
t-BuLi x

Br Br
A B

Br ROH Br
x x

Li
D C

! The game plan:

– The rearrangement of B to C requires a TS geometry which allows an endocyclic reaction.

– If the geometry requirement can not be met, an intermolecular reaction is expected.

– A geometrical dependance for the reaction can be established by a change in the tether length

– Therefore, a lack of geometrical dependance would reveal no change in the intra/intermolecularity

of the reaction with systematic variation of the tether.
Beak, P.; Allen, D. J. J. Am. Chem. 1992, 114, 3420.
 Probing the Transition Structure Geometry: The Endocyclic Restriction Test

! How to distinguish between an inter– and intramolecular reaction? 79Br

intramolecular
rearrangement
products
I Li 81Br
x x
ROH x
79Br 79Br D
D
t-BuLi

I Li intermolecular 79Br
x x
D
D D rearrangement x
81Br D
81Br products

ROH 81Br

Double-Double Labelling Experiments

79Br

x
D
D
Intramolecular– isotopic distribution will be the same as the reactants

81Br
Intermolecular– a statistically distributed ratio of products will be
x
obtained which can be determined by MS D
D

Beak, P.; Allen, D. J. J. Am. Chem. 1992, 114, 3420.

 Probing the Transition Structure Geometry: The Endocyclic Restriction Test

! Intermolecular reactions are observed for systems that would have a 6 or 8 membered endocyclic
transition structure

I
Br
Br n
intermolecular
Br
only n
Li Br
I

Br proposed transition state

! Intramolecular reactions is allowed in an 18 membered endocyclic transition state demonstrating the

geometrical requirement for large bond angles around the entering and leaving groups for SN2 reaction

intermolecular (55%) O
O 11 I
intramolecular (45%)
Br
Br

Li
proposed transition state

Beak, P.; Allen, D. J. J. Am. Chem. 1992, 114, 3420.

 Probing the Transition Structure Geometry: The Endocyclic Restriction Test

! Intermolecular reactions are observed for systems that would have a 6 or 8 membered endocyclic
transition structure

I
Br
Br n
intermolecular
Br
only n
Li Br
I

Br proposed transition state

! Intramolecular reactions is allowed in an 18 membered endocyclic transition state demonstrating the

geometrical requirement for large bond angles around the entering and leaving groups for SN2 reaction

intermolecular (55%) O
O 11 I
intramolecular (45%)
Br
Br

Li
proposed transition state

Beak, P.; Allen, D. J. J. Am. Chem. 1992, 114, 3420.

 Probing the Transition Structure Geometry: Other Mechanistic Conclusions

! Authors discount the four–centered transition state mechanism on the basis that the requisite C–Br–C
bond would be small and an inrtamolecular transition state would have been accessible

I Li

Br Br

proposed transition state

! SET mechanism is also ruled out as there was no intramolecular exchange observed in two cases

Br

Br Li
I

Br proposed intermediate

Beak, P.; Allen, D. J. J. Am. Chem. 1992, 114, 3420.

 The Mechanism of Lithium–Halogen Exchange: Conclusions

! Mechanism of lithium–halogen exchange is still under debate in the literature, the

balance of evidence suggests:

Br or I nucleophilic ("ate–complex") mechanism

R

1° alkyl iodide nucleophilic ("ate–complex") mechanism

2° alkyl iodide nucleophilic ("ate–complex")/ radical competition

alkyl bromide radical mechanism

! What of the reactivity of lithium–halogen exchange relative to other processes?

 The Mechanism of Lithium–Halogen Exchange: Conclusions

! Mechanism of lithium–halogen exchange is still under debate in the literature, the

balance of evidence suggests:

Br or I nucleophilic ("ate–complex") mechanism

R

1° alkyl iodide nucleophilic ("ate–complex") mechanism

2° alkyl iodide nucleophilic ("ate–complex")/ radical competition

alkyl bromide radical mechanism

! What of the reactivity of lithium–halogen exchange relative to other processes?

 A Competition: Reaction of Organolithium Reagents

! Lithium-Halogen exchange versus proton transfer

t-BuLi (2 eq)
I MeOH (2 eq) H Me
pentane:ether
–78 °C, 5 min 97% yield <0.3

! Exchange can exceed the rate of proton transfer in some cases*

Me Me Me Me Me Me
Me Me
O O
O O
B B
n-BuLi (1 eq)

MeOH
Br N H N
–100 °C
OBn PMB OBn PMB

~ 80% yield

Bailey, W. F.; Patricia, J. J.; Nurmi, T. T.; Wang, W. Tetrahedron Lett. 1996, 27, 1861.
*Rob Knowles unpublished results
 A Competition: Reaction of Organolithium Reagents

! Lithium–Halogen exchange versus nucleophilic addition:

O
O Br O Li O
O n-BuLi (1 eq) O O
O
NHR
O THF O
N O
N
R –95 to –105 °C
R 82% yield

n-Bu
OH
O
observed when
NHR
using excess n-BuLi
O

! Exchange reaction is more rapid than addition in some cases

OMe
OMe OMe
MeO
O MeO MeO
t-BuLi (2 eq) O
OMe
MeO N OMe
THF, –78 °C MeO
MeO N
I Me
Li Me
O

64% yield

Adhen, I. S.; Ahuja, J. R. Tetrahedron Lett. 1992, 33, 5431.

Paleo, M. R.; Castedo, L.; Dominguez, D. J. Org. Chem. 1993, 109, 2763.
 Applications in Total Synthesis
! Synthesis of Scopadulic Acid B
Competitive lithium–halogen exchange is faster with the aryliodide than reaction with the terminal aldehyde

I Br H I
O OH
t-BuLi (1.05 eq)
H low yield
Me Et2O, –78 °C
OTBS OTBS
Me

! Transmetallation gives a more nucleophilic organometallic species

Br H BrMg H I
t-BuLi (1.05 eq) MgBr2•OEt2 O

Me Et2O, –78 °C Et2O, 0 °C Me H

OTBS

Me
O
I
OH Me
steps
Scopadulcic Acid B
H

OTBS
Me Me OH
85% yield O
HO

Overman, L.; Ricca, D. J.; Tran, V. D. J. Am. Chem. 1997, 50, 12031
 Applications in Total Synthesis

! Synthesis of Morphine: Formation of the tetracyclic core

Br
OMe
OMe
Br OMe
O n-BuLi (2.2 eq) O O–
Li O
OH H
THF, –78 °C Br O– Br
PhO2S PhO2S
PhO2S H Li

OMe
A OH
H+ OH
O C
H B steps OH
O
D
SO2Ph MeN

60% yield Morphine

Toth, J. E.; Fuchs, P. L. J. Org. Chem. 1997, 53, 473.

 Applications in Total Synthesis
! Synthesis of the Kedarcidin Chromaphore Aglycon by an anionic transannular ring closure

i-PrO OMOM i-PrO OMOM

O O
MeO MeO

OMe OMe HN H
* HN H
3Å MS; LHMDS (3.05 eq), –96 °C;
Cl N Cl N
*
t-BuLi (1.05 eq), THF, –96 °C; O
O
O O AcOH (12 eq) O O

OTIPS 38–45% yield OTIPS

OH
Br * OH
TBSO TBSO

steps
! Deuterium-labelling experiment: [D4]acetic acid quench
i-PrO OR
i-PrO OMOM

The authors O
O MeO
MeO conclude that the OMe HN H
OMe HN H transsannular Cl N
Cl N D (! 60%)
cyclization
O
O had proceeded O O
O O
through a
tetraanion OR
OTIPS OH
OH intermediate RO
TBSO O
8
D (> 90%) Kedarcidin Chromophore Aglycon

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41, 1062.
 The Mechanism of Lithium–Halogen Exchange: Conclusions

! Mechanism of lithium–halogen exchange is still under debate in the literature, the

balance of evidence suggests:

Br or I nucleophilic ("ate–complex") mechanism

R

1° alkyl iodide nucleophilic ("ate–complex") mechanism

2° alkyl iodide nucleophilic ("ate–complex")/ radical competition

alkyl bromide radical mechanism

! Lithium-halogen reactions have found broad use by synthetic organic chemists

! What of the reactivity of lithium–halogen exchange relative to other processes?